title: Risk factors for development of dementia in a unique six-year cohort study. I. An exploratory, pilot study of involvement of the E4 allele of apolipoprotein E, mutations of the hemochromatosis-HFE gene, type 2 diabetes, and stroke.
abstract: Risk factors for dementia development are not well-defined. We evaluated several factors alone and in combination in a unique cohort of Caucasian volunteers over an approximately 6-year observation window using a nested case/control design. Factors included: apolipoprotein E (ApoE) gene variants (the E4 allele is the strongest confirmed genetic predisposing factor for Alzheimer's disease), the hemochromatosis-HFE gene mutations (H63D and C282Y), diabetes, and stroke. At study entry, subjects were ≥65 years of age (M ± SD = 73.0 ± 4.9), had an MMSE score ≥24, and no evidence of cerebrovascular disease or current depression. Genotyping was completed on 163 available DNA samples from three different groups at the study end: those who still had normal cognitive function; those who had developed dementia; and those with Mild Cognitive Impairment (MCI). Analyses were interpreted at the 95% confidence level without Bonferroni corrections. In the subgroup with dementia, all cases of diabetes were type 2 and present at study entry, whereas all strokes occurred during the study. The results highlight apparently synergistic interactions between genetic and medical risk factors for dementia development, gender differences in risk factors, and involvement of HFE mutations. Having E4 (i.e., either of E3/4 or E4/4), C282Y, H63D, diabetes, or stroke alone did not attain significance. Significant predisposing factors with post-hoc power ≥80% were: E4 homozygosity (E4/4)males+females, odds ratio (OR) = 56.0); E4+diabetes (males+females, OR = 13.7; E4+H63D+diabetes (females, OR = 52.0); E4+stroke (males, OR = 46.5). The importance of preventing diabetes and stroke to ward off dementia and the possible role of iron dysmetabolism in dementia are discussed.
authors.affiliation: Departments of Physiology and Obstetrics & Gynaecology, University of Toronto, Toronto ON, Canada, Surrey Place Centre, Toronto ON, Canada.
authors.forename: Maire
authors.initials: M
authors.lastname: Percy
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Somerville
authors.forename: Mark
authors.initials: M
authors.lastname: Hicks
authors.forename: Angeles
authors.initials: A
authors.lastname: Garcia
authors.forename: Teresa
authors.initials: T
authors.lastname: Colelli
authors.forename: Emily
authors.initials: E
authors.lastname: Wright
authors.forename: Julia
authors.initials: J
authors.lastname: Kitaygorodsky
authors.forename: Amy
authors.initials: A
authors.lastname: Jiang
authors.forename: Valerie
authors.initials: V
authors.lastname: Ho
authors.forename: Alyssa
authors.initials: A
authors.lastname: Parpia
authors.forename: Michael K
authors.initials: MK
authors.lastname: Wong
mesh_terms: D000368:Aged; D000483:Alleles; D053327:Apolipoprotein E4 / Q000235:genetics*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000235:genetics; D015331:Cohort Studies; D003704:Dementia / Q000175:diagnosis / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010865:Pilot Projects; D012307:Risk Factors; D020521:Stroke / Q000175:diagnosis / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins
keywords: Alzheimer's disease; C282Y; H63D; HFE mutations; apolipoprotein E; cohort study; dementia; hemochromatosis; iron; mild cognitive impairment; risk factors; stroke; type 2 diabetes mellitus